Received: 20 April 2022 Revised: 30 May 2022 Accepted: 26 June 2022

DOI: 10.1111/jcpe.13691

ORIGINAL ARTICLE

A multi-centre randomized controlled trial comparing

connective tissue graft with collagen matrix to increase
soft tissue thickness at the buccal aspect of single
implants: 1-year results

Jan Cosyn | Célien Eeckhout | Thomas De Bruyckere | Aryan Eghbali |

Stijn Vervaeke | Faris Younes | Véronique Christiaens

Department of Periodontology and Oral

Implantology, Faculty of Medicine and Health Abstract
Sciences, Oral Health Sciences, Ghent Aim: To compare connective tissue graft (CTG) with collagen matrix (CMX) in terms of
University, Ghent, Belgium
increase in buccal soft tissue profile (BSP) at 1 year when applied at single implant sites.
Correspondence Materials and Methods: Patients with a single tooth gap in the anterior maxilla and
Jan Cosyn, Department of Periodontology and
Oral Implantology, Faculty of Medicine and horizontal mucosa defect were enrolled in a multi-centre randomized controlled trial.
Health Sciences, Oral Health Sciences, Ghent All sites had a bucco-palatal bone dimension of at least 6 mm, received a single
University, Corneel Heymanslaan 10, B-9000
Ghent, Belgium. implant and an immediate implant restoration using a full digital workflow. Sites were
Email: [email protected] randomly allocated to the control (CTG) or test group (CMX) to increase buccal soft
Funding information tissue thickness. The primary outcome was the increase in BSP at 1 year when com-
Osteology Foundation, Grant/Award Number: pared with the pre-operative situation based on superimposed digital surface models.
18-178; Universiteit Gent, Grant/Award
Number: BOF.STG.2019.0004.01 The changes in BSP over time were registered at a buccal area of interest reaching
from 0.5 mm below the soft tissue margin to 4 mm more apical. Secondary outcomes
included patient-reported, clinical and aesthetic outcomes.
Results: Thirty patients were included per group (control: 50% females, mean age
50.1; test: 53% females, mean age 48.2). The increase in BSP at 1 year was 0.98 mm
(98.3% confidence interval [CI]: 0.75–1.20) for CTG and 0.57 mm (98.3% CI: 0.34 to
0.79) for CMX. The mean difference of 0.41 mm (98.3% CI: 0.12 to 0.69) in favour of
CTG was significant (p < .001). Based on an arbitrarily chosen threshold for success
of 0.75 mm increase in BSP, 89.7% of the patients in the control group and 10% of
the patients in the test group were successfully treated (odds ratio = 77.90; 95% CI:
13.52 to 448.80; p < .001). Sites treated with CMX demonstrated 0.89 mm (98.3%
CI: 0.49 to 1.30) more shrinkage between postop and 1 year than sites treated with
CTG. In addition, CMX resulted in significantly more marginal bone loss (0.39 mm;
95% CI: 0.05 to 0.74; p = .026) than CTG. There were no significant differences
between the groups in terms of patients' aesthetic satisfaction (p = .938), probing
depth (p = .917), plaque (p = .354), bleeding on probing (p = .783), midfacial reces-
sion (p = .915), Pink Esthetic Score (p = .121) and Mucosal Scarring Index (p = .965).
Conclusions: CTG remains the gold standard to increase soft tissue thickness at implant
sites. Clinicians need to outweigh the benefits of CMX against considerable resorption
of the graft. This study was registered in ClinicalTrials.gov (NCT04210596).

J Clin Periodontol. 2022;49:911–921. wileyonlinelibrary.com/journal/jcpe © 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. 911
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912 COSYN ET AL.

KEYWORDS
collagen matrix, connective tissue graft, dental implant, single tooth, soft tissue

Clinical Relevance
Scientific rationale for study: Connective tissue graft (CTG) has been well documented to increase
buccal soft tissue thickness. However, a second surgical site is needed, which increases surgery
time and may lead to complications such as palatal bleeding, pain, swelling, infection or necrosis.
Recently, a collagen matrix (CMX) has been developed.
Principal findings: CMX is less effective than CTG in augmenting soft tissues at the buccal aspect
of single implants up to 1 year of follow-up.
Practical implications: CTG remains the gold standard.

1 | I N T RO DU CT I O N CTG. However, this conclusion should be interpreted with caution

because it was based on only two randomized controlled trials
Systematic reviews have demonstrated considerable horizontal (RCTs) with short follow-ups. More recently, Tavelli et al. (2021)
resorption of the alveolar process after tooth extraction (Tan published a network meta-analysis on the topic. The network
et al., 2012; Couso-Queiruga et al., 2021). Given the narrow dimen- model demonstrated significantly higher estimates in terms of gain
sion of the ridge, this is mainly problematic in the pre-maxilla. There- in soft tissue thickness for CTG (1.13 mm) when compared with
fore, augmentation procedures are often required when replacing a CMX (0.76 mm). Although highly relevant, this conclusion was only
tooth with an implant in the aesthetic zone. Bone augmentation is based on single-centre RCTs. Since soft tissue augmentation is con-
clearly indicated when an implant is not completely covered by bone. sidered a technique-sensitive procedure, also the surgeon could
Minor buccal bone defects result in soft tissue concavities, which can have a relevant impact on effectiveness. Only multi-centre studies
be effectively treated by means of soft tissue augmentation (Cairo can elucidate this.
et al., 2019; Raghoebar et al., 2021; Tavelli et al., 2021; Thoma Recently, a multi-centre RCT has been published comparing CTG
et al., 2021). The outcome of soft tissue augmentation is clinically rel- with a cross-linked porcine-derived CMX (Cosyn, Eeckhout,
evant because thicker tissues support peri-implant health (Thoma et al., 2021). Soft tissue augmentation was performed to treat minor
et al., 2018; Tavelli et al., 2021) and result in higher patient satisfac- horizontal defects at the buccal aspect of single implants. Although
tion and superior aesthetics (Stefanini et al., 2021). Soft tissue aug- surgeons applied 0.85 mm thicker grafts when using CMX, sites trea-
mentation also seems to favour soft tissue stability in the vertical ted with CMX demonstrated 0.78 mm more shrinkage after 3 months.
dimension, regardless of the timing of implant placement (Raghoebar The final increase in BSP at the cervical aspect was 1.15 mm for CTG
et al., 2021; Seyssens et al., 2021). and 0.85 mm for CMX. In addition, CMX resulted in more marginal
Connective tissue graft (CTG) is considered the gold standard bone loss, deeper pockets and more midfacial recession than CTG.
approach to increase buccal soft tissue thickness around implants. These 3-month results are indicative of significant inflammation at
Profilometric evaluation has shown to be the most accurate method CMX-treated sites. Further follow-up is needed to investigate
to assess this (Cosyn, Wessels, et al., 2021) and resulted in a linear whether these clinical parameters deteriorate, stabilize or improve. In
increase in buccal soft tissue profile (BSP) at the cervical aspect of addition, longer follow-up is required to assess the clinical effective-
1.19 mm after 1 year (De Bruyckere et al., 2020) and 0.99 mm after ness of both augmentation procedures and to make clinical
3 years (Bouckaert et al., 2022). Although predictable, CTG requires a recommendations.
second surgical site for tissue harvesting, which increases surgery time The present article presents the 1-year follow-up data of an ear-
and may lead to complications such as palatal bleeding, pain, swelling, lier published multi-centre RCT (Cosyn, Eeckhout, et al., 2021). The
infection or necrosis (Griffin et al., 2006). In addition, there are limits primary objective was to compare CTG with CMX in terms of increase
in terms of connective tissue that can be harvested from the palate or in BSP at 1 year when applied at single implant sites demonstrating a
tuberosity. In order to overcome these limitations, xenogeneic colla- minor horizontal alveolar defect.
gen matrices have been developed (Thoma et al., 2012, 2014;
Rothamel et al., 2014). However, most of the studies included in a
recent systematic review showed similar patient-reported outcomes 2 | M A T E R I A L S A N D M ET H O D S
between autogenous grafts and substitutes (Stefanini et al., 2021;
Thoma et al., 2021). 2.1 | Study design and patient selection
When it comes to effectiveness, Cairo et al. (2019) published a
systematic review comparing CTG with collagen matrix (CMX). Their The present study was designed as a follow-up of patients previously
meta-analysis demonstrated on average 0.3 mm thicker tissues after enrolled in a multi-centre superiority RCT comparing CTG with CMX
 1600051x, 2022, 9, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jcpe.13691 by Egyptian National Sti. Network (Enstinet), Wiley Online Library on [21/05/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
COSYN ET AL. 913

(Cosyn, Eeckhout, et al., 2021). Patients in need of a single implant 2.3 | Treatment procedures and
restoration in the pre-maxilla were enrolled between September 2019 postoperative care
and September 2020 on the basis of inclusion and exclusion criteria.
Inclusion criteria were as follows: Details on the treatment procedures and postoperative care can be
found in an earlier paper (Cosyn, Eeckhout, et al., 2021).
• At least 21 years old. In brief, a low-dose small-field cone-beam computed tomography
• Good oral hygiene, defined as full-mouth plaque score ≤25% and intra-oral scan were taken and imported in designated software
(O'Leary et al., 1972). (DTX Studio®, Nobel Biocare AB, Göteborg, Sweden) to fabricate a
• Presence of a single tooth gap in the pre-maxilla (15–25) with both stereolithographic surgical guide and screw-retained CAD/CAM pro-
neighbouring teeth present. visional restoration (TempShell®, Nobel Biocare AB).
• Failing tooth at least 3 months prior to enrolment removed. On the day of surgery, a full-thickness mucoperiosteal flap was
• At least 5 mm of keratinized mucosa available at the single raised by means of a crestal incision at the single tooth gap and sulcular
tooth gap. incisions at the neighbouring teeth. A dental implant (NobelReplace CC
• Class I defect at the single tooth gap as clinically assessed (bucco- PMC® TiUnite, Nobel Biocare AB) was installed using a surgical guide.
palatal loss of tissue with a normal apicocoronal ridge height) Thereupon, a sealed envelope was opened, containing the assignment
(Seibert, 1983). for either one of two treatment modalities:
• Bucco-palatal bone dimension of at least 6 mm at the central and
crestal aspect of the single tooth gap as assessed on Cone Beam • Control group: autogenous CTG.
Computed Tomography (CBCT) to ensure complete embedding of • Test group: CMX (Geistlich Fibro-Gide®, Geistlich Pharma AG,
an implant by bone. Wolhusen, Switzerland).
• Signed informed consent.
In the control group, a CTG was harvested from the palatal
Exclusion criteria were as follows: mucosa in the pre-molar area by means of the single incision tech-
nique as described by De Bruyckere et al. (2015). The optimal size of
• Systemic diseases. the CTG was tailored to the dimensions of the site. The palatal wound
• Smoking. was closed with double-cross sutures (Vicryl® Plus 4/0, Ethicon, Cin-
• Periodontal disease. cinnati, OH). In the test group, CMX was used. Its dimensions were
• Untreated caries lesions. adapted to the defect using a scalpel and scissors. After the release of
• Need for horizontal bone augmentation at the time of implant muscle tension, the graft was brought into the buccal envelope and
placement. fixed with two single sutures (Seralon 6/0, Serag Wiessner, Naila,
Germany) onto the buccal mucosa.
The study was approved by the Ethical Committee of Ghent Uni- After installation of the screw-retained provisional restoration
versity Hospital (B670201940413) and registered in ClinicalTrials.gov (TempShell®, Nobel Biocare AB), tension-free primary wound closure
(NCT04210596). It was conducted in accordance with the ethical was achieved. Sutures were removed after 2 weeks. The provisional
standards of the Declaration of Helsinki in 1975, as revised in 2013. crown was replaced by a permanent crown by the general dentist after
The study was reported following the guidelines of the CONSORT 3 months.
statement (Schulz et al., 2010).

2.4 | Changes in BSP

2.2 | Randomization, allocation concealment and
blinding An intra-oral scan (Trios, 3shape, Copenhagen, Denmark) was taken at
the following time points in each patient: T0 (pre-op), T1 (immediately
Six experienced and calibrated implant surgeons working in differ- postop), T2 (3 months) and T3 (1 year). The obtained digital surface
ent periodontal practices in Belgium were selected to participate models in STL (Surface Tessellation Language) format were imported
in this multi-centre RCT. Details can be found in an earlier paper into designated software (SMOP, Swissmeda AG, Zurich, Switzerland)
(Cosyn, Eeckhout, et al., 2021). Patients were randomly assigned to analyse volumetric and profilometric changes by a blinded examiner.
to either the control group (CTG) or the test group (CMX). A study-relevant area of interest (AOI) at the buccal aspect was
Block randomization was performed per centre, meaning that each selected for each augmented site. The AOI reached from 0.5 mm
centre received an equal number of sealed envelopes for every below the soft tissue margin to 4 mm more apical. In the mesiodistal
treatment group. Group allocation was revealed after implant dimension, the AOI reached from the mesial to the distal line angle of
installation and remained concealed for the evaluating examiner the implant crown. The AOI varied between patients due to individual
and statistician to allow for unbiased registrations and analyses, anatomic differences but was kept constant in each patient across
respectively. time points.
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914 COSYN ET AL.

F I G U R E 1 (a–d) Case illustrating a patient of the control group (connective tissue graft [CTG]). (a). Occlusal view of the digital surface model
at T0 (yellow) showing a Seibert Class I defect; (b). Volumetric and profilometric changes in the area of interest (orange) between T0 (yellow) and
T1 (green); (c). Volumetric and profilometric changes in the area of interest (orange) between T0 (yellow) and T2 (grey); (d). Volumetric and
profilometric changes in the area of interest (orange) between T0 (yellow) and T3 (blue). (e–h) Case illustrating the above-mentioned for a patient
of the test group (collagen matrix [CMX]).

Each time point was compared with the pre-op model (T0–T1, complications that occurred in the early stages of healing were
T0–T2, and T0–T3) by superimposing the two models using the best- reported in a previous paper (Cosyn, Eeckhout, et al., 2021).
fit algorithm at the unchanged adjacent tooth surfaces. A mean volu-
metric change (in cubic millimetre) within the AOI for each patient at
T1, T2 and T3 was calculated by the software. As the size of the AOI 2.6.2 | Marginal bone loss
(in square millimetre) differed among patients, the mean volumetric
change was divided by the AOI, resulting in the mean change in BSP. Peri-apical radiographs were taken with the long-cone paralleling
Figure 1 illustrates volumetric and profilometric changes in the AOI in technique at implant placement and 1 year. Measurements were per-
a patient from the control group and test group. formed by a blinded examiner in designated software (DBSWIN Imag-
ing Software, Dürr Dental SE, Bietigheim-Bissingen, Germany). The
distance from the implant-abutment interface to the first bone-to-
2.5 | Patient-reported outcome measures implant contact (the so-called bone level) was assessed at the mesial
and distal aspects of each implant. To control for enlargement, the
Patients' aesthetic satisfaction was registered 1 year after surgery by implant length served as the reference distance. Marginal bone loss
means of visual analogue scale (VAS). All patients were offered the fol- was calculated at 1 year by subtracting bone levels at 1 year from
lowing question: “How satisfied are you with the aesthetic outcome of bone levels at implant placement. Mesial and distal values were aver-
the soft tissues surrounding the implant?” Patients responded on a aged to receive one value per implant.
100 mm line with “most unsatisfied” and “most satisfied” as extremes.

2.6.3 | Probing depth, plaque and bleeding

2.6 | Clinical outcomes on probing

2.6.1 | Complications Probing depth was registered using a manual probe (University North
Carolina Probe PCPUNC 156, Hu-Friedy, Frankfurt, Germany) by the
Any biological or technical complication that occurred was recorded treating surgeon at four locations (mesio-buccal, buccal, disto-buccal
by the treating surgeon. In the present paper, only complications that and oral) around the implant at 1 year. Measurements were rounded
occurred after 3 months of follow-up were reported. Technical up to the nearest 0.5 mm. A mean value was calculated per implant.
 1600051x, 2022, 9, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jcpe.13691 by Egyptian National Sti. Network (Enstinet), Wiley Online Library on [21/05/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
COSYN ET AL. 915

Plaque and bleeding on probing were assessed by the treating Inter-assessor reliability on marginal bone loss, PES and MSI was
surgeon at four locations (mesio-buccal, buccal, disto-buccal and oral) assessed based on 20 randomly selected cases using the intra-class cor-
around the implant at 1 year. Each location was scored 0 or 1 (absence relation coefficient (ICC). The level of significance was set at 0.05.
or presence of plaque or bleeding on probing, respectively). Both
parameters were expressed as a percentage.
3 | RE SU LT S

2.7 | Aesthetic outcomes 3.1 | Patient groups

2.7.1 | Midfacial recession The CONSORT flow diagram is shown in Figure 2. In the control group,
15 males and 15 females with a mean age of 50.1 (SD 17.0) years par-
Midfacial recession was calculated at 1 year on digital surface models of ticipated. The test group consisted of 14 males and 16 females with a
T1 (immediately postop) and T3 (1 year) in the same software (SMOP, mean age of 48.2 (SD 16.3) years. Details on implant positions, length,
Swissmeda AG). The distance from the incisal edge of the crown to the diameter and initial horizontal defect dimension per group can be found
buccal mucosal margin (the so-called midfacial soft tissue level) was in an earlier paper (Cosyn, Eeckhout, et al., 2021).
determined at the centre of each implant to the nearest 0.01 mm. Midfa- One implant in the control group was lost at 1-week follow-up
cial recession was calculated by subtracting midfacial soft tissue levels at due to mobility. All other implants survived up to 1 year. One patient
1 year from post-operative midfacial soft tissue levels. Positive values in the test group dropped out at 1 year due to unwillingness to return
indicated recession; negative values indicated vertical regrowth. Midfa- despite several attempts. One patient in the control group still func-
cial recession was assessed by a blinded examiner. tioned with the provisional restoration at 1 year.

2.7.2 | Pink Esthetic Score and Mucosal Scarring 3.2 | Changes in BSP
Index
In the control group, the volumetric increase was 39.85 mm3 at T1,
The Pink Esthetic Score (PES) (Fürhauser et al., 2005) and Mucosal 30.86 mm3 at T2 and 26.35 mm3 at T3. In the test group, the volume
Scarring Index (MSI) (Wessels et al., 2019) were registered by a gain was 50.93 mm3 at T1, 22.55 mm3 at T2 and 16.92 mm3 at T3.
trained and blinded examiner using frontal and occlusal clinical pic- Dividing volumetric soft tissue changes by the AOI resulted in
tures taken at 1 year. The PES results in a score from 0 (worst aes- increase in BSP. The raw data are shown in Figure 3 per patient, treat-
thetic outcome) to 14 (perfect aesthetic outcome). The MSI results in ment group, time point and centre. Estimated marginal means are
a score from 0 (no scar) to 10 (most extreme scar). illustrated per treatment group and time point in Figure 4.
A significant treatment effect (between-group difference) could be
shown at the different time points. At T1, the increase in BSP was
2.8 | Statistical analysis 0.47 mm higher in the test group than in the control group (98.3% CI:
0.02 to 0.92; p = .012). At T2 and T3, an additional increase in BSP of
A sample size calculation indicated 25 patients to be included per 0.30 mm (98.3% CI: 0.03 to 0.63; p = .027) and 0.41 mm (98.3% CI:
group. To compensate for dropouts, this number was increased to 0.12 to 0.69; p < .001), respectively, was observed in favour of the con-
30 patients per group. Details on the sample size calculation can be trol group. Successful soft tissue augmentation was arbitrarily defined as
found in an earlier paper (Cosyn, Eeckhout, et al., 2021). SPSS Statis- an increase in BSP of at least 0.75 mm at 1 year. Based on this criterion,
tics 27 (SPSS Inc., Chicago, IL) was used for data analysis. A linear 89.7% of the patients in the control group and 10% of the patients in
mixed model was applied to assess the changes in BSP, taking into the test group were successfully treated. The difference between the
account the clustering of patients within centres. Treatment group, groups was significant (OR = 77.90; 95% CI: 13.52 to 448.80; p < .001).
time and their interaction were modelled as fixed factors, patient A significant time effect (within-group difference) was observed in
and centre as random factors. Estimated marginal means and confi- both groups (p = .001 in the control group and p < .001 in the test group).
dence intervals (CIs) were calculated per treatment group and per In the control group, the increase in BSP immediately post-surgery
time point. Since the analysis included three time points (T1, T2 and (T1) was 1.43 mm (98.3% CI: 1.10 to 1.76). A shrinkage of 0.27 mm
T3), a Bonferroni correction was applied, and 98.3% CIs were calcu- (98.3% CI: 0.09 to 0.64; p = .107) was observed between T1 and T2,
lated. Binary logistic regression was adopted to compare the groups pointing to an increase in BSP of 1.15 mm (98.3% CI: 0.89 to 1.41).
in terms of treatment success. The latter was arbitrarily defined as Between T2 and T3, a further shrinkage of 0.18 mm (98.3% CI: 0.07
an increase in BSP of at least 0.75 mm at 1 year. Odds ratio (OR) and to 0.43; p = .144) was seen, pointing to a final increase in the BSP of
95% CI were calculated. 0.98 mm (98.3% CI: 0.75 to 1.20).
A linear mixed model was also applied to analyse secondary out- In the test group, the increase in BSP immediately post-
comes at 1 year. Ninety-five percent CIs were calculated. surgery (T1) was 1.90 mm (98.3% CI: 1.58 to 2.23). A significant
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916 COSYN ET AL.

FIGURE 2 CONSORT flow diagram. CMX, collagen matrix; CTG, connective tissue graft.

shrinkage of 1.05 mm (98.3% CI: 0.69 to 1.41; p < .001) was 3.4 | Clinical outcomes
observed between T1 and T2, pointing to an increase in BSP of
0.85 mm (98.3% CI: 0.60 to 1.10). Between T2 and T3, a further 3.4.1 | Complications
shrinkage of 0.28 mm (98.3% CI: 0.03 to 0.54, p = .006) was seen,
pointing to a final increase in BSP of 0.57 mm (98.3% CI: 0.34 One crown fracture occurred in the control group due to crown
to 0.79). detachment from the titanium abutment. No other complications
A significant treatment*time interaction (p < .001) was found, occurred.
implying that the changes in BSP over time were significantly different
between CTG and CMX. Sites treated with CMX demonstrated
0.89 mm (98.3% CI: 0.49 to 1.30) more shrinkage between T1 and T3 3.4.2 | Marginal bone loss
than sites treated with CTG.
The ICC for assessing inter-assessor reliability on marginal bone loss
was 0.992 (p < .001), suggesting excellent agreement between dupli-
3.3 | Patient-reported outcome measures cate measurements.
Mean marginal bone loss was 0.66 mm in the control group and
There was no significant difference between the groups in patient's 1.05 mm in the test group at 1 year. The mean difference of
aesthetic satisfaction at 1 year (p = .938). Mean VAS was 89.64 in the 0.39 mm (95% CI: 0.05 to 0.74) in favour of the control group was
control group and 89.36 in the test group (Table 1). significant (p = .026) (Table 1).
 1600051x, 2022, 9, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jcpe.13691 by Egyptian National Sti. Network (Enstinet), Wiley Online Library on [21/05/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
COSYN ET AL. 917

F I G U R E 3 Increase in buccal soft tissue profile per patient, treatment group, time point and centre (raw data). CMX, collagen matrix; CTG,
connective tissue graft.

F I G U R E 4 Increase in buccal
soft tissue profile per treatment
group and time point (estimated
marginal means; 98.3%
confidence interval). CMX,
collagen matrix; CTG, connective
tissue graft.

3.4.3 | Probing depth, plaque and bleeding on Mean bleeding on probing was 17.70% in the control group and
probing 16.33% in the test group at 1 year. The mean difference of 1.37%
(95% CI: 8.58 to 11.32) was not significant (p = .783) (Table 1).
Mean probing depth was 3.12 mm in the control group and 3.14 mm
in the test group at 1 year. The mean difference of 0.02 mm (95% CI:
0.41 to 0.45) was not significant (p = .917) (Table 1). 3.5 | Aesthetic outcomes
Mean plaque was 8.03% in the control group and 12.07% in the
test group at 1 year. The mean difference of 4.03% (95% CI: 4.63 to Mean midfacial recession was 0.38 mm in the control group and
12.69) was not significant (p = .354) (Table 1). 0.37 mm in the test group at 1 year. The mean difference of
 1600051x, 2022, 9, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jcpe.13691 by Egyptian National Sti. Network (Enstinet), Wiley Online Library on [21/05/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
918 COSYN ET AL.

TABLE 1 Secondary outcomes

CTG CMX Difference p-Value

Patient-reported outcome measures
Patients' aesthetic appreciation (VAS) 89.64 (82.33–96.94) 89.36 (82.09–96.63) 0.28 ( 6.80–7.35) .938
Clinical outcomes
Marginal bone loss (mm) 0.66 (0.35–0.96) 1.05 (0.75–1.36) 0.39 (0.05–0.74) .026
Probing depth (mm) 3.12 (2.46–3.78) 3.14 (2.49–3.80) 0.02 ( 0.41–0.45) .917
Plaque (%) 8.03 (1.56–14.50) 12.07 (5.69–18.45) 4.03 ( 4.63–12.69) .354
Bleeding on probing (%) 17.70 (9.13–26.27) 16.33 (7.84–24.82) 1.37 ( 8.58–11.32) .783
Aesthetic outcomes
Midfacial recession (mm) 0.38 (0.24–0.53) 0.37 (0.23–0.52) 0.01 ( 0.16–0.18) .915
Pink Esthetic Score (/14) 11.99 (10.88–13.10) 11.23 (10.11–12.36) 0.75 ( 1.72–0.21) .121
Mucosal Scarring Index (/10) 1.34 (0.40–2.27) 1.36 (0.41–2.31) 0.02 ( 1.03–1.08) .965

Note: Estimated marginal mean (95% confidence interval), mean difference (95% confidence interval) and p-value between groups.
Abbreviations: CMX, collagen matrix; CTG, connective tissue graft; VAS, visual analogue scale.

0.01 mm (95% CI: 0.16 to 0.18) was not significant (p = .915) potential indications, clinicians need to outweigh the benefits of CMX
(Table 1). against considerable resorption of the graft.
The ICC for assessing inter-assessor reliability on PES and MSI Clinical studies with profilometric evaluations after CTG applica-
was 0.721 (p = .004) and 0.672 (p = .010), respectively, suggesting tion at the cervical aspect of single implants are emerging. De Bruyck-
moderate agreement between duplicate measurements. ere et al. (2020) reported a linear increase in BSP of 1.19 mm at
Mean PES was above 11 and did not differ between the groups 1 year. Huber et al. (2018) registered profilometric changes between
(p = .121). Mean MSI was below 1.5 and did not differ between the permanent crown installation and 1-year follow-up, pointing to a
groups (p = .965). Hence, the peri-implant aesthetic outcome was median loss of 0.2 mm from an initial increase of 0.94 mm (Zeltner
pleasing in both groups (Table 1). et al., 2017). Rojo et al. (2020) reported 0.03–0.04 mm tissue loss
between permanent crown installation and 1-year follow-up from an
initial increase of 0.69–0.79 mm. By and large, these findings indicate
4 | DISCUSSION that only minor changes occur after permanent crown installation, and
that CTG may result in an increase in buccal soft tissue thickness of
The primary objective of this multi-centre RCT was to compare CTG about 0.5–1.5 mm after 1 year. The results of the CTG group in the
with CMX in terms of increase in BSP at 1 year when applied at single present study are in line with these observations.
implant sites demonstrating a minor horizontal mucosa defect. A CMX used in the present study was evaluated by the Zürich
porcine-derived cross-linked CMX was used for this purpose, which group in a series of publications (Thoma et al., 2016, 2020; Zeltner
has shown to be most resistant to biodegradation when compared et al., 2017; Huber et al., 2018; Naenni et al., 2018). Huber et al.
with other collagen matrices (Vallecillo et al., 2021). This paper reports (2018) registered profilometric changes between permanent crown
on the changes over a 1-year period. The final increase in BSP was installation and 1-year follow-up, pointing to a median loss of 0.1 mm
0.98 mm (98.3% CI: 0.75 to 1.20) for CTG and 0.57 mm (98.3% CI: from an initial increase of 0.59 mm (Zeltner et al., 2017). Interestingly,
0.34 to 0.79) for CMX. The mean difference of 0.41 mm (98.3% CI: there were no significant differences between CTG and CMX at any
0.12 to 0.69) in favour of CTG was significant (p < .001). Based on an time point (Thoma et al., 2016, 2020; Zeltner et al., 2017; Huber
arbitrarily chosen threshold for success of 0.75 mm increase in BSP at et al., 2018; Naenni et al., 2018). These findings suggest similar soft
1 year, 89.7% of the patients in the control group and 10% of the tissue dynamics for CTG and CMX, which seem to contrast the results
patients in the test group were successfully treated. The difference of the present study. In this context, it should be emphasized that the
between the groups was significant (OR = 77.90; 95% CI: 13.52 to Zürich group reported on 20 patients who were treated in one centre
448.80; p < .001). Hence, CTG remains the gold standard for soft tis- to participate in a non-inferiority RCT. In contrast, 60 patients were
sue augmentation at the buccal aspect of implants. Based on the treated in six centres and participated in the present superiority RCT.
advantages of CMX, specific indications may justify its use. These The latter provides information on the clinical effectiveness of both
include soft tissue augmentation in pain-sensitive patients, in patients procedures when applied by different surgeons and may therefore
requiring concise surgery because of anxiety or medical reasons, and show higher external validity. In addition, a non-inferiority trial is a
when surgery is performed by inexperienced clinicians because CTG priori designed to assess similarity, whereas a superiority trial is
harvesting requires more surgical skills. Notwithstanding these designed to assess difference.
 1600051x, 2022, 9, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jcpe.13691 by Egyptian National Sti. Network (Enstinet), Wiley Online Library on [21/05/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
COSYN ET AL. 919

As earlier described by Cosyn, Eeckhout, et al. (2021), CMX and final draft. Stijn Vervaeke: Research protocol; surgeon;
resulted in more marginal bone loss, deeper pockets and more midfa- data interpretation; second and final draft. Faris Younes: Research
cial recession than CTG in the early stages of healing. These findings protocol; surgeon; data interpretation; second and final draft. Véro-
are indicative of significant inflammation at CMX-treated sites. Cross- nique Christiaens: Research protocol; surgeon; data interpretation;
linking can increase inflammation (Thoma et al., 2012; Rothamel second and final draft.
et al., 2014). Yet, in contrast to the present study, this was not always
clinically observed (Thoma et al., 2017), which may be explained by AC KNOW LEDG EME NT S
differences in sample size. The fact that probing depth and midfacial The authors want to thank Dr. Ellen Deschepper for the statistical
recession did not differ anymore between the groups at 1 year sug- analysis.
gests a decline in inflammatory response. Less encouraging is that
marginal bone loss remained significantly higher at CMX-treated sites FUNDING INF ORMATI ON
at 1 year. Mean marginal bone loss amounted to 1.05 mm at these Prof. Cosyn has collaboration agreements with Nobel Biocare AB
sites, which exceeds what has been described for the implant system (Göteborg, Sweden) and Straumann (Basel, Switzerland). Dr. Stijn Ver-
used (Lambrechts et al., 2021). This parameter is important to monitor vaeke has a collaboration agreement with Denstply Sirona (Mölndal,
in the longer term, because a recent study has identified early peri- Sweden). The project was supported by a grant (18-178) from the
implant bone loss as a significant predictor of peri-implantitis in the Osteology Foundation, Switzerland, and by a grant (BOF.
long term (Windael et al., 2021). STG.2019.0004.01) from Ghent University, Belgium. Biomaterials
For a correct interpretation of the present study, the following were delivered free of charge by Geistlich Pharma AG (Wolhusen,
limitations need to be addressed. First, graft thickness was not Switzerland).
standardized among patients and clinicians. On the other hand,
standardization may not be possible because the thickness of a CONFLIC T OF INT ER E ST
graft should be based on the horizontal extent of the defect, which The authors declare that there is no conflict of interest.
obviously varies among patients. The fact that clinicians applied
0.85 mm thicker grafts when using CMX may be considered a bias. DATA AVAILABILITY STAT EMEN T
This is a consequence of the fact that CMX is offered in 6 mm The data that support the findings of this study are available from the
thickness by the manufacturer. Second, the sample size calculation corresponding author upon reasonable request.
was based on the primary study outcome. Hence, the present study
may have been underpowered for some secondary outcome vari- ET HICS S TAT E MENT
ables. Third, some secondary outcomes were assessed by the treat- The study was approved by the Ethical Committee of Ghent Uni-
ing surgeon and not by a blinded examiner for practical reasons, versity Hospital (B670201940413) and registered in ClinicalTrials.
which could have introduced information bias. Also, radiographs gov (NCT04210596). It was conducted in accordance with the ethi-
were not standardized using individual splints, which could have cal standards of the Declaration of Helsinki in 1975, as revised
had an impact on the results of marginal bone loss. Finally, the pre- in 2013.
sent paper reported on 1-year outcomes. Longer follow-up is
needed to elucidate the effectiveness and safety of CMX. Monitor-
OR CID
ing marginal bone loss is crucial in this respect.
Jan Cosyn https://orcid.org/0000-0001-5042-2875
Aryan Eghbali https://orcid.org/0000-0002-1515-8965
Stijn Vervaeke https://orcid.org/0000-0002-1416-6787
5 | C O N CL U S I O N
Faris Younes https://orcid.org/0000-0003-3716-5119

CTG remains the gold standard to increase soft tissue thickness at

RE FE RE NCE S
implant sites. Special care patients and surgery performed by inexperi-
Bouckaert, E., De Bruyckere, T., Eghbali, A., Younes, F.,
enced clinicians may be indications for the use of CMX. Notwith-
Wessels, R., & Cosyn, J. (2022). A randomized controlled trial
standing these potential indications, clinicians need to outweigh the comparing guided bone regeneration to connective tissue graft
benefits of CMX against considerable resorption of the graft. to re-establish buccal convexity at dental implant sites: Three-
year results. Clinical Oral Implants Research, 33, 461–471.
https://doi.org/10.1111/clr.13906
AUTHOR CONTRIBUTIONS
Cairo, F., Barbato, L., Selvaggi, F., Baielli, M. G., Piattelli, A., &
Jan Cosyn: Principal investigator; funding; coordinator; research Chambrone, L. (2019). Surgical procedures for soft tissue aug-
protocol development; surgeon; data interpretation; second and final mentation at implant sites. A systematic review and meta-
draft. Célien Eeckhout: Literature review; data collection; data inter- analysis of randomized controlled trials. Clinical Implant Dentistry
and Related Research, 21(6), 1262–1270. https://doi.org/10.
pretation; first and second draft. Thomas De Bruyckere: Research
1111/cid.12861
protocol; surgeon; data interpretation; second and final draft. Aryan Cosyn, J., Wessels, R., Garcia Cabeza, R., Ackerman, J., Eeckhout, C., &
Eghbali: Research protocol; surgeon; data interpretation; second Christiaens, V. (2021). Soft tissue metric parameters, methods and
 1600051x, 2022, 9, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jcpe.13691 by Egyptian National Sti. Network (Enstinet), Wiley Online Library on [21/05/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
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Randomized controlled clinical study comparing a volume-stable